Abstract 6093: IDE161, a potential first-in-class clinical candidate PARG inhibitor, selectively targets homologous-recombination-deficient and PARP inhibitor resistant breast and ovarian tumors
Authors: Monah Abed, Diana Muñoz, Vidya Seshadri, Steve Federowicz, Arjun A. Rao, Deepthi Bhupathi, Marya Liimatta, Rita Ousterhout, Firoz Jaipuri, Claire Neilan, Mark Lackner, Mike White, Zineb Mounir
Journal: Cancer Research (2023)

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) were the first clinically approved drugs designed to exploit synthetic lethality. Despite initial responses, patients harboring homologous recombination (HR) alterations that receive PARPi develop treatment resistance, which has generated a need for additional therapies targeting homologous recombination deficient (HRD) tumors. Poly (ADP-Ribose) glycohydrolase (PARG) plays a key role in the resolution of PARP1/2-dependent DNA damage repair through hydrolysis of Poly (ADP-ribose) (PAR) chains and consequent release of DNA repair protein complexes from chromatin. In culture, the accumulation of PAR chains in the absence of a functional PARG enzyme causes delayed repair of DNA breaks resulting in increased sensitivity to alkylating agents and ionizing radiation. Notably, some HRD cell models have shown differential sensitivity to PARGi vs PARPi, suggesting that PARGi may overcome some PARPi resistance mechanisms. The ability of PARGi to exacerbate replication deficiencies nominates it as a potential therapeutic target for a broad range of cancer types with genomic instability. IDE161 is an orally bioavailable small molecule inhibitor of PARG. Biochemical and cellular assays demonstrate that IDE161 is a potent inhibitor of PAR chain hydrolysis and has anti-proliferative activity in breast and ovarian HRD cancer cell lines with both inherent and acquired PARPi resistance. IDE161 anti-proliferative effects were associated with induction of mitotic arrest and activation of the DNA damage response pathway, suggesting the position of PARG in the DNA repair cycle remains essential in the context of some PARPi resistance mechanisms. Furthermore, profiling of IDE161 across a panel of 264 molecularly characterized cancer cell lines indicated that PARGi may show benefit beyond HRD and in indications other than ovarian and breast. Nonclinical studies in cell line and patient derived xenograft models of breast, ovarian, and gastric tumor types harboring defects in the HR pathway demonstrated anti-tumor activity in response to IDE161. Consistent with in vitro findings, we observed IDE161 antitumor activity in PARPi resistant xenograft models. Moreover, studies in cell lines, tumors and tissues revealed that dose and time-dependent accumulation of PAR chains serves as a robust proximal pharmacodynamic biomarker indicative of PARG target engagement. IDE161 is a novel targeted therapy that exploits the synthetic lethal relationship between PARG and genomic instability, thus leading to selective anti-proliferative effects in tumors harboring defects in the HR pathway. Citation Format: Monah Abed, Diana Muñoz, Vidya Seshadri, Steve Federowicz, Arjun A. Rao, Deepthi Bhupathi, Marya Liimatta, Rita Ousterhout, Firoz Jaipuri, Claire Neilan, Mark Lackner, Mike White, Zineb Mounir. IDE161, a potential first-in-class clinical candidate PARG inhibitor, selectively targets homologous-recombination-deficient and PARP inhibitor resistant breast and ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6093.